The present invention relates to 6-substituted-7-heteroquinoxalinecarboxylic acid derivatives and their addition salts effective for the therapy of disorder of cerebral nerve cells as antagonists against excitatory amino acid receptors, in particular, as selective antagonists against AMPA receptor in non-NMDA receptor, processes for the preparation of both, and a medicinal composition containing these compounds.
The glutamic acid being excitatory amino acid is a main excitatory transmitter substance in the central nervous system of vertebrates, and is known as an amino acid contained most rich in brain. It is known, however, that, when releasing from nervous axon terminals exceeding the physiological threshold, it excessively excites the glutamic acid receptor of post-synapse to cause the death of nerve cells. This is called excitotoxicity.
In recent years, it has been clarified that the death of nerve cells due to glutamic acid concerns deeply in various diseases of cerebral nerve such as cerebral hemorrhage, head trauma, epilepsy, Huntington""s disease, Parkinson""s disease, amyotrophic lateral sclerosis and Alzheimer""s disease. It is considered therefore that, if such excitotoxicity could be prevented effectively, a potential to the therapy for these intractable diseases, for which there are virtually no therapeutic means at present, would be opened.
Roughly classifying, the glutamic acid receptor is divided into ion channel type receptor and G protein-binding type receptor, and this ion channel type receptor is further divided into NMDA (N-methyl-D-aspartic acid) receptor and non-NMDA receptor. Moreover, the latter non-NMDA receptor is classified into AMPA (xcex1-amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid) receptor and KA (kainic acid) receptor. Studies on these excitatory amino acid receptors are being put forward, and, above all, with the drug with antagonism against AMPA receptor in non-NMDA receptor, it is known that the adverse effects (learning and memory disturbances, schizophrenia-like symptom, etc.), which the drugs (MK-801 etc.) with antagonism against NMDA receptor have, are not expressed (Neurosci. Biobehav. Rev., 1992, 16, 13-24; J. Pharmacol. Exp. Ther., 1958, 245, 969-974), and that the protective effect on cerebral nerve can be expected even by the administration after ischemia (Science, 1990, 247, 571-574).
Moreover, with the compounds with quinoxalinedione structure and with antagonism against AMPA receptor such as NBQX, drawbacks of causing kidney disturbance that is considered based on physicochemical properties, and the like are reported (J. Cereb. Blood Flow Metab., 1994, 14, 251-261), hence they cannot be said to be satisfactory compounds.
Now, as the compounds with similar structure to quinoxalinecarboxylic acid derivatives, compounds represented by a general formula (15) 
(wherein X independently denotes chlorine or bromine atom, and R denotes methyl or ethyl group), described in Jpn. Kokai Tokkyo Koho JP 56,005,416 as compounds with antiviral function by Lily Co., and compounds represented by a general formula (16) 
(wherein R and R1 independently denote halogen atoms, R2 denotes hydrogen, methyl or ethyl group, R3 denotes hydrogen, methyl, ethyl, hydroxyethyl, benzyl or ethoxycarbonylmethyl group, and R4 denotes cyclooctyl, norbonyl group, etc.), described in Jpn. Kokai Tokkyo Koho JP 56,081,569 as compounds with antiviral function similarly by Lily Co., are known. However, these compounds have 6- and 7-positions of symmetric type, it is not known that they have the antagonism against AMPA receptor in excitatory amino acid receptors of the inventive compounds, and they have different structure from that of the inventive compounds.
Furthermore, compounds represented by a general formula (17) 
(wherein R and R4 independently denote hydrogens, nitro or methoxy groups, R1 and R2 independently denote hydrogens, nitro or methoxy groups or halogen atoms (one of R, R1, R2 and R4 is a group other than hydrogen, in the case of R1 and R2 being not nitro groups or methoxy groups, R1 and R2 are independently halogen atoms together and R and R4 are hydrogens, and, in the case of one of R, R1, R2 and R4 is nitro group, either one of R1 and R2 is methoxy group), R3 denotes hydrogen, lower alkyl group which may be substituted with halogen, lower cycloalkyl group, lower alkenyl group or 2-chloroethyl group, and n denotes 0 or 2), described in Jpn. Kokai Tokkyo Koho JP 55,069,514 as compounds with antiviral function similarly by Lily Co., are known. However, disclosed compounds have different structure from that of the inventive compounds, and it is not described that they have the antagonism against AMPA receptor in excitatory amino acid receptors which the inventive compounds have.
Moreover, in WO92-11245 described by Warner-Lambert Co., as compounds with antagonism against excitatory amino acid receptor, compounds represented by a general formula (18) 
(wherein Y denotes oxygen, sulfur or nitrogen atom, R1, R2, R11 and R12 denote hydrogens, lower alkyl groups which may be substituted with halogen, halogen atoms, trifluoromethyl groups, cyano groups, nitro groups, methylthio groups, lower alkenyl groups, lower alkynyl groups, sulfonamide groups, etc., or arbitrary two of R1, R2, R11 and R12 may form a ring (6-membered ring or heterocycle which may contain heteroatom), and X denotes sulfonylamide group which may have substituents, etc.) are known. However, in these compounds, those with asymmetric substituents at 6- and 7-position of quinoxaline as the inventive compounds are not disclosed, and, with disclosed compounds, the antagonism against AMPA is not shown and the disclosed antagonism against glycine is not considered to be sufficient as well.
The invention is to provide compounds with antagonism against receptors of glutamic acid that is considered to be an etiology bringing about the memory disorder and dementia due to said diseases and selective death of cells, in particular, with high affinity and selectivity against AMPA receptor in non-NMDA receptor and protective effect on cerebral nerve cells.
As a result of diligent studies exploring an antagonist against excitatory amino acid receptors effective for the therapy of disorder of cerebral nerve cells, in particular, a selective antagonist against AMPA receptor in non-NMDA receptor, aiming at the development of novel therapeutic agent for the disorder of cerebral nerve cells, the inventors have found that the inventive 6-substituted-7-heteroquinoxalinecarboxylic acid derivatives and addition salts thereof have excellent antagonism against AMPA receptor.
Namely, according to the invention, it has been found that 6-substituted-7-heteroquinoxalinecarboxylic acid derivatives represented by a general formula (1) 
(wherein A denotes a single bond or methylene (CH2),
Y denotes a nitrogen atom or xe2x95x90CHxe2x80x94,
V denotes a single bond or methylene (CH2),
T denotes a hydroxyl group, amino group, lower alkoxycarbonyl group, carboxyl group, aldehyde group, general formula (2) 
(wherein X denotes an oxygen atom or sulfur atom, R denotes an aralkyl group, phenyl group, naphthyl group, 5- or 6-membered heterocycle and its condensed ring (these may have one or more substituents on aromatic ring or heterocycle), lower alkyl group which may be substituted with halogen atom, or cycloalkyl group), or general formula (3) 
(wherein X denotes an oxygen atom or sulfur atom, R denotes an aralkyl group, phenyl group, naphthyl group, 5- or 6-membered heterocycle and its condensed ring. (these may have one or more substituents on aromatic ring or heterocycle), lower alkyl group which may be substituted with halogen atom, or cycloalkyl group),
Q denotes a halogen atom, lower alkyl group or lower alkoxy group, and
R1 denotes a hydroxyl group or lower alkoxy group), and addition salts thereof have excellent antagonism against AMPA receptor, leading to the completion of the invention.
In the general formula (1) of the inventive compounds, preferably, compounds, R1 being hydroxyl group or ethoxy group and A being single bond, are mentioned. More preferably, compounds, Q being chloro group, R1 being hydroxyl group, V being methylene (CH2), X being oxygen atom and R being 4-carboxyphenyl group in the general formula (2) and general formula (3) for T are mentioned.
As these preferable compounds, compounds shown below, namely, ethyl 6-chloro-3,4-dihydro-7-(3-formylpyrrole-1-yl)-3-oxoquinoxaline-2-carboxylate, ethyl 3,4-dihydro-7-(3-formylpyrrole-1-yl)-6-methoxy-3-oxoquinoxaline-2-carboxylate, ethyl 7-(3-formylpyrrole-1-yl)-6-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-2-carboxylate, ethyl 7-(3-formylpyrrole-1-yl)-6-fluoro-3-oxo-1,2,3,4-tetrahydroquinoxaline-2-carboxylate, ethyl 7-(3-(aminomethyl)pyrrole-1-yl)-6-chloro-3-oxo-1,2,3,4-tetrahydroquinoxaline-2-carboxylate hydrochloride, ethyl 6-chloro-7-(3-(((4-ethoxycarbonylphenyl)aminocarbonylamino)methyl)pyrrole-1-yl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-2-carboxylate, ethyl 6-chloro-3,4-dihydro-7-(3-(((4-ethoxycarbonylphenyl)aminocarbonylamino)methyl)pyrrole-1-yl)-3-oxoquinoxaline-2-carboxylate, ethyl 6-chloro-3,4-dihydro-7-(3-(((4-ethoxycarbonyl-2-fluorophenyl)aminocarbonylamino)methyl)pyrrole-1-yl)-3-oxoquinoxaline-2-carboxylate, 7-(3-(((4-carboxyphenyl)aminocarbonylamino)methyl)pyrrole-1-yl)-6-chloro-3,4-dihydro-3-oxoquinoxaline-2-carboxylic acid, 7-(3-(((4-carboxyphenyl)aminocarbonylamino)methyl)pyrrole-1-yl)-3,4-dihydro-6-methyl-3-oxoquinoxaline-2-carboxylic acid, 7-(3-(((4-carboxyphenyl)aminocarbonylamino)methyl)pyrrole-1-yl)-3,4-dihydro-6-methoxy-3-oxoquinoxaline-2-carboxylic acid, 7-(3-(((4-carboxyphenyl)aminocarbonylamino)methyl)pyrrole-1-yl)-3,4-dihydro-6-fluoro-3-oxoquinoxaline-2-carboxylic acid, 7-(3-(((4-carboxy-2-fluorophenyl)aminocarbonylamino)methyl)pyrrole-1-yl)-6-chloro-3,4-dihydro-3-oxoquinoxaline-2-carboxylic acid, ethyl 6-chloro-3,4-dihydro-7-(4-(hydroxymethyl)imidazole-1-yl)-3-oxoquinoxaline-2-carboxylate, ethyl 6-chloro-3,4-dihydro-7-(4-(((4-ethoxycarbonylphenyl)carbamoyloxy)methyl)imidazole-1-yl)-3-oxoquinoxaline-2-carboxylate, ethyl 6-chloro-3,4-dihydro-7-(4-(((4-ethoxycarbonylmethylphenyl)carbamoyloxy)methyl)imidazole-1-yl)-3-oxoquinoxaline-2-carboxylate, 7-(4-(((4-carboxyphenyl)carbamoyloxy)methyl)imidazole-1-yl)-6-chloro-3,4-dihydro-3-oxoquinoxaline-2-carboxylic acid, 7-(4-(((4-carboxy-2-fluorophenyl)carbamoyloxy)methyl)imidazole-1-yl)-6-chloro-3,4-dihydro-3-oxoquinoxaline-2-carboxylic acid, 7-(4-(((4-carboxyphenyl)aminocarbonylamino)methyl)imidazole-1-yl)-6-chloro-3,4-dihydro-3-oxoquinoxaline-2-carboxylic acid, 7-(4-(((4-carboxy-2-fluorophenyl)aminocarbonylamino)methyl)imidazole-1-yl)-6-chloro-3,4-dihydro-3-oxoquinoxaline-2-carboxylic acid, 7-(4-(((4-carboxymethylphenyl)aminocarbonylamino)methyl)imidazole-1-yl)-6-chloro-3,4-dihydro-3-oxoquinoxaline-2-carboxylic acid, and the like can be mentioned.
In the description of the general formula (1) of the invention, xe2x80x9cfor substituentsxe2x80x9d in the phrase of xe2x80x9caralkyl group, phenyl group, naphthyl group, 5- or 6-membered heterocycle and its condensed ring (these may have one or more substituents on aromatic ring or heterocycle)xe2x80x9d, halogen atom, hydroxyl group, lower alkyl group which may be substituted with halogen atom, lower alkoxy group, lower alkylthio group, lower alkoxycarbonyl group, nitro group, amino group which may be substituted, cyano group, carboxyl group, aldehyde group, lower alkanoic acid group, etc. are mentioned, for xe2x80x9clower alkyl groupsxe2x80x9d, straight chain or branched ones with carbon atoms of 1 to 6 such as methyl, ethyl, n-propyl and iso-propyl are mentioned, for xe2x80x9ccycloalkyl groupsxe2x80x9d, ones with carbon atoms of 3 to 7 such as cyclopropyl, cyclopentyl and cyclohexyl are mentioned, for xe2x80x9chalogen atomsxe2x80x9d, fluorine, chlorine, bromine and iodine are mentioned, xe2x80x9clower alkoxy groupsxe2x80x9d, straight chain or branched ones with carbon atoms of 1 to 4 such as methoxy, ethoxy -and propoxy are mentioned, for xe2x80x9clower alkylthio groupsxe2x80x9d, straight chain or branched ones with carbon atoms of 1 to 6 such as methylthio, ethylthio and propylthio are mentioned, for xe2x80x9clower alkoxycarbonyl groupsxe2x80x9d, straight chain or branched ones with carbon atoms of 1 to 4 such as methoxycarbonyl and ethoxycarbonyl are mentioned, and, for xe2x80x9camino groups which may be substitutedxe2x80x9d, amino groups may be substituted with acyl group or arylsulfonyl group, for example, acetyl, methanesulfonyl, phenylsulfonyl, etc., or they may be substituted with lower alkyl group which may be substituted with 1 to 2 halogen atoms, phenyl group which may have 1 to 2 substituents or aralkyl group which may have 1 to 2 substituents. The substituents referred to so here are xe2x80x9csubstituentsxe2x80x9d as described above.
Furthermore, in the description, xe2x80x9cheterocyclesxe2x80x9d in the phrase of xe2x80x9caralkyl group, phenyl group, naphthyl group, 5- or 6-membered heterocycle and its condensed ring (these may have one or more substituents on aromatic ring or heterocycle)xe2x80x9d are saturated or unsaturated monocyclic or polycyclic heterocycle groups which may have one or more substituents and which can contain one or more nitrogen, oxygen or sulfur atoms, and, for example, pyrrolidyl, piperidyl, piperazyl, morpholyl, thiomorpholyl, furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidyl, pyridazyl, pyrazyl, etc. are mentioned. xe2x80x9cIts condensed ringxe2x80x9d represents benzene-condensed rings of said xe2x80x9cheterocyclesxe2x80x9d and, for example, indolyl, tetrahydroquinolyl, benzoxazolidinyl, benzothiazolidinyl, benzofuranyl, benzothienyl, benzimidazolyl, quinolyl, isoquinolyl, quinazolyl, quinoxalyl, cinnolyl, etc. are mentioned.
The compounds of the invention are prepared, for example, through preparative processes shown below.
Compounds represented by the general formula (1) can be synthesized by reacting compounds represented by a general formula (4) 
(wherein A, Y, V, T, Q and R1 are as described above), for 1 to 24 hours at 20 to 120xc2x0 C. in a suitable solvent, for example, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, benzene, toluene or the like, using an oxidizing agent, for example, DDQ (dichlorodicyanoquinone). They can also be synthesized by reacting compounds represented by the general formula (4) for 1 to 24 hours at 20 to 120xc2x0 C. in a suitable solvent, for example, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, benzene, toluene, ethanol, methanol or the like, using an organic base, for example, triethylamine, ethyldiisopropylamine or the like, or an inorganic base, for example, potassium carbonate, sodium carbonate, potassium hydroxide or sodium hydroxide. Moreover, compounds represented by the general formula (1) can be obtained by reacting compounds represented by a general formula (5) 
(wherein A, Y, V, T, Q and R1 are as described above, and R2 denotes a lower alkyl group which may be substituted with halogen atom or aralkyl group which may have one or more substituents), for 0.5 to 72 hours at 20 to 120xc2x0 C. without solvent or in a suitable solvent, for example, water, acetic acid, methanol or the like, using a suitable acid, for example, hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid, mixed acid thereof or the like to synthesize compounds, R1 in the general formula (1) being hydroxyl group alkoxy group among compounds represented by the general formula (5), those compounds are reacted for 0.5 to 72 hours at 20 to 120xc2x0 C. without solvent or in a suitable solvent, for example, water, acetic acid, methanol or the like, using a suitable acid, for example, hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid or the like to deprotect R2, and then reacted for 0.5 to 10 hours at 20 to 100xc2x0 C. in a solvent of water, methanol, ethanol or the like, using a suitable alkali, for example, potassium hydroxide, sodium hydroxide or the like to synthesize compounds, R1 in the general formula (1) being hydroxyl group.
Moreover, compounds, R1 being lower alkoxy group among compounds represented by the general formula (1), can be obtained by reacting those compounds for 0.5 to 10 hours at 20 to 100xc2x0 C. in a suitable solvent of water, methanol, ethanol or the like, using a suitable alkali, for example, potassium hydroxide, sodium hydroxide or the like to synthesize compounds, R1 in the general formula (1) being hydroxyl group.
Moreover, compounds, Y being represented by xe2x95x90CHxe2x80x94 among compounds represented by the general formula (1), can also be synthesized by reacting compounds represented by a general formula (6) 
(wherein A, Q and R1 are as described above), with compounds represented by a general formula (7) 
(wherein T and V are as described above, and R3 denotes a lower alkyl group which may be substituted with halogen atom or aralkyl group which may have one or more substituents), for 0.5 to 5 hours at 20 to 120xc2x0 C. without solvent or in a suitable solvent such as tetrahydrofuran, benzene, toluene, acetic acid, ethanol, methanol or the like (suitable inorganic or organic acid, for example, hydrochloric acid, sulfuric acid, p-toluene sulfonic acid or the like may be added).
Moreover, compounds, T being represented by the general formula (2) or general formula (3) among compounds represented by the general formula (1), can also be synthesized by reacting compounds represented by a general formula (8) 
(wherein T1 denotes hydroxyl group or amino group, and A, Y, V, Q and R1 are as described above), with compounds represented by a general formula (9)
Zxe2x80x94Nxe2x95x90Cxe2x95x90Xaxe2x80x83xe2x80x83(9)
(wherein Z denotes an aralkyl group, phenyl group, naphthyl group, 5- or 6-membered heterocycle and its condensed ring (these may have one or more substituents on aromatic ring or heterocycle), lower alkyl group which may be substituted with halogen atom or cycloalkyl group, and Xa denotes an oxygen or sulfur atom), for 0.5 to 24 hours at 20 to 120xc2x0 C. in a suitable solvent, for example, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, benzene, toluene or the like, without base or using a suitable organic base, for example, triethylamine or the like, Moreover, they can also be synthesized by converting compounds represented by a general formula (10)
Zxe2x80x94A1xe2x80x94Dxe2x80x83xe2x80x83(10)
(wherein Z denotes an aralkyl group, phenyl group, naphthyl group, 5- or 6-membered heterocycle and its condensed ring (these may have one or more substituents on aromatic ring or heterocycle), lower alkyl group which may be substituted with halogen atom or cycloalkyl group, A1 denotes single bond, and D denotes an amino group, carboxyl group, amide group or lower alkoxycarbonyl group), to isocyanic (isothiocyanic) esters or carbamic chlorides through already known process, in place of the general formula (9), and then reacting with general formula (8) similarly to general formula (9).
For example, in the case of D being amino group, they can be converted to carbamic chlorides or isocyanic (isothiocyanic) esters by reacting with phosgene (thiophosgene), phosgene dimer (2,2,2-trichloromethyl chloroformate) or its homologue (4-nitrophenyl chloroformate etc.) for 1 to 5 hours at xe2x88x9210 to 50xc2x0 C. in a suitable solvent, for example, tetrahydrofuran, dioxane, benzene, toluene or the like, without base or using a suitable organic base, for example, triethylamine or the like. Further, they can be converted to isocyanic (isothiocyanic) esters by using Curtius rearrangement reaction or Schmidt rearrangement reaction after converted carboxyl group to acid azide in the case of D being carboxyl group, and by using Hofmann rearrangement reaction in the case of D being amide group. Moreover, in the case of D being carboxyl group, it is also possible to convert to isocyanic (isothiocyanic) esters in one pot using DPPA (diphenylphosphoryl azide).
Moreover, compounds represented by the general formula (1) can also be synthesized by reacting compounds represented by a general formula (11) 
(wherein A, Y, V, T and Q are as described above), with ketomalonic diesters represented by a general formula (12) 
(wherein R4 denotes a lower alkyl group), for 2 to 12 hours at 25 to 100xc2x0 C. in a suitable solvent, for example, ethanol, methanol, tetrahydrofuran or the like.
Moreover, compounds, Y being CH among compounds represented by the general formula (4), can also be synthesized by reacting compounds represented by a general formula (13) 
(wherein A, Q and R1 are as described above), with compounds represented by the general formula (7) 
(wherein T, V and R3 are as described above), for 0.5 to 5 hours at 20 to 120xc2x0 C. without solvent or in a suitable solvent such as tetrahydrofuran, benzene, toluene, acetic acid, ethanol, methanol or the like (suitable inorganic or organic acid, for example, hydrochloric acid, sulfuric acid, tosyl acid or the like may be added).
Moreover, compounds, T being represented by the general formula (2) or general formula (3) among compounds represented by the general formula (4), can also be synthesized by reacting compounds represented by a general formula (14) 
(wherein A, Y, V, T1, Q and R1 are as described above), with compounds represented by the general formula (9)
Zxe2x80x94Nxe2x95x90Cxe2x95x90Xaxe2x80x83xe2x80x83(9)
(wherein Z and Xa are as described above), for 1 to 24 hours at 20 to 120xc2x0 C. in a suitable solvent, for example, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, benzene, toluene or the like, without base or using a suitable organic base, for example, triethylamine or the like. Moreover, they can also be synthesized by converting compounds represented by the general formula (10)
Zxe2x80x94A1xe2x80x94Dxe2x80x83xe2x80x83(10)
(wherein Z and D are as described above), to isocyanic (isothiocyanic) esters or carbamic chlorides through already known process, in place of the general formula (9), and then reacting with general formula (14) similarly to general formula (9).
For example, in the case of D being amino group, they can be converted to carbamic chlorides or isocyanic (isothiocyanic) esters by reacting with phosgene (thiophosgene), phosgene dimer (2,2,2-trichloromethyl chloroformate) or its homologue (4-nitrophenyl chloroformate etc.) for 1 to 5 hours at xe2x88x9210 to 50xc2x0 C. in a suitable solvent, for example, tetrahydrofuran, dioxane, benzene, toluene or the like, without base or using a suitable organic base, for example, triethylamine or the like. Further, they can be converted to isocyanic (isothiocyanic) esters by using Curtius rearrangement reaction or Schmidt rearrangement reaction after converted carboxyl group to acid azide in the case of D being carboxyl group, and by using Hofmann rearrangement reaction in the case of D being amide group. Moreover, in the case of D being carboxyl group, it is also possible to convert to isocyanic (isothiocyanic) esters in one pot using DPPA (diphenylphosphoryl azide).
Moreover, compounds, Q being halogen atom among compounds represented by the general formula (5), can be synthesized by reacting compounds represented by a general formula (19) 
(wherein A, Y, V, T, R1 and R2 are as described above), with diazotizing agent, for example, sodium nitrite or the like for 0.5 to 1 hour at 0 to 50xc2x0 C. in a suitable solvent, for example, acetic acid, water, mixed solvent thereof or the like, and then reacting with halogenating agent, for example, potassium chloride, potassium bromide, potassium iodide or the like for 0.5 to 2 hours at 25 to 50xc2x0 C. Moreover, they can also be synthesized by reacting compounds represented by the general formula (19) with alkyl nitrite, for example, t-butyl nitrite or the like and cupper (I or II) halide, for example, cupper chloride, cupper bromide, cupper iodide or the like for 1 to 5 hours at 25 to 50xc2x0 C. in a suitable solvent, for example, dimethyl sulfoxide, acetonitrile or the like.
Moreover, compounds, A being methylene (CH2) among compounds represented by the general formula (5), can also be synthesized by reacting compounds represented by a general formula (20) 
(wherein Q, R1 and R2 are as described above, and Xb denotes a halogen atom), with compounds represented by a general formula (21) 
(wherein Y, V and T are as described above), for 2 to 10 hours at 25 to 110xc2x0 C. in a suitable solvent, for example, N,N-dimethylformamide, acetonitrile or the like in the presence of an organic base, for example, triethylamine or the like.
Moreover, compounds, A being single bond among compounds represented by the general formula (6), can be synthesized by reacting compounds represented by a general formula (22) 
(wherein Q and R1 are as described above), for 1 to 7 hours at 25 to 100xc2x0 C. in a suitable solvent, for example, ethanol, dilute hydrochloric acid, acetic acid or mixed solvent thereof in the presence of tin chloride, zinc, iron, sodium hydrosulfite or the like.
Moreover, compounds, A being methylene (CH2) among compounds represented by the general formula (6), can be synthesized by reacting compounds represented by a general formula (23) 
(wherein Q, R1 and R2 are as described above), for 1 to 12 hours at 20 to 100xc2x0 C. in a suitable solvent, for example, carbon tetrachloride, chloroform, acetic acid or the like, using a halogenating agent, for example, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine or the like to convert to compounds represented by the general formula (20) 
(wherein Q, R1, R2 and Xb are as described above), then by reacting these with compounds represented by a general formula (24)
R5R6xe2x80x94NHxe2x80x83xe2x80x83(24)
(wherein R5 and R6 identically or differently denote hydrogen atoms or protective groups of amino group), for 1 to 48 hours at 20 to 160xc2x0 C. in a suitable solvent, for example, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, benzene, toluene or the like, without base or using a suitable inorganic or organic base, for example, sodium hydride, sodium carbonate, potassium carbonate, triethylamine or the like to convert to compounds represented by a general formula (25) 
(wherein A, Q, R1, R2, R5 and R6 are as described above), and further by reacting these for 0.5 to 24 hours at 20 to 100xc2x0 C. in a suitable solvent, for example, methanol, ethanol or the like, using a suitable acid, for example, hydrochloric acid, sulfuric acid or the like.
Moreover, compounds represented by the general formula (8) can be synthesized by reacting compounds represented by the general formula (14) 
(wherein A, Y, V, T1, Q and R1 are as described above), for 1 to 24 hours at 20 to 120xc2x0 C. in a suitable solvent, for example, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, benzene, toluene or the like, using an oxidizing agent, for example, DDQ(dichlorodicyanoquinone).
Moreover, they can also be synthesized by reacting compounds represented by the general formula (14) for 1 to 24 hours at 20 to 120xc2x0 C. in a suitable solvent, for example, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, benzene, toluene, ethanol, methanol or the like, using an organic base, for example, triethylamine, ethyldiisopropylamine or the like or inorganic base, for example, potassium carbonate, sodium carbonate, potassium hydroxide or sodium hydroxide.
Moreover, compounds represented by the general formula (11) can be synthesized, for example, by deprotecting compounds represented by a general formula (26) 
(wherein A, Y, V, T and Q are as described above, and, for P1P2, one denotes hydrogen atom and the other denotes protective group of amino group, or both denote protective groups of amino group), according to usual process (general formula 27), and then by reducing nitro group to convert to phenylenediamine (general formula 11). 
(wherein A, Y, V, T, Q, P1 and P2 are as described above)
The deprotection of general formula (26) can be performed by reacting for 3 to 72 hours at 20 to 120xc2x0 C. without solvent or in a suitable solvent, for example, water, methanol, ethanol or the like, using a suitable acid, for example, hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid or the like, or by reacting for 0.5 to 10 hours at 20 to 100xc2x0 C. using a suitable alkali, for example, potassium hydroxide, sodium hydroxide or the like.
The reduction of nitro group of general formula (27) can also be performed through reduction by catalytic hydrogenation, that is, by hydrogenating at 25 to 80xc2x0 C. and at atmospheric pressure to 5 atm (507 KPa) in a suitable solvent, for example, ethanol, methanol, acetic acid or the like in the presence of a suitable catalyst, for example, palladium on carbon, platinum oxide, rhodium on alumina or the like. Also, it can be performed by reacting at 25 to 100xc2x0 C. in a suitable solvent, for example, ethanol, dilute hydrochloric acid, acetic acid or mixed solvent thereof in the presence of tin chloride, zinc, iron, sodium hydrosulfite or the like.
Moreover, compounds, A being single bond and R1 being ethoxy group among compounds represented by the general formula (13), can be synthesized through processes shown by following scheme. 
(wherein Q is as described above)
Compounds (28) synthesizable through already known process are reacted with diethyl ketomalonate for 1 to 6 hours at 20 to 120xc2x0 C. in a suitable solvent, for example, ethanol, methanol, tetrahydrofuran or the like to convert to compounds (29), these compounds are subject to nitration, that is, reacted for 0.5 to 2 hours at xe2x88x9210 to 80xc2x0 C. without solvent or in a suitable solvent, for example, concentrated sulfuric acid, carbon disulfide or acetic acid solvent, using a suitable nitrating agent, for example, concentrated nitric acid, fuming nitric acid, potassium nitrate or the like to convert to compounds represented by compounds (29), and these are reduced through catalytic hydrogenation, that is, by hydrogenating at 20 to 80xc2x0 C. and at atmospheric pressure to 5 atm (507 KPa) in a suitable solvent, for example, ethanol, methanol, acetic acid or the like in the presence of a suitable catalyst, for example, palladium on carbon, platinum oxide, rhodium on alumina or the like, thus making it possible to synthesize.
Moreover, compounds represented by the general formula (14) can also be synthesized by reducing compounds represented by the general formula (8) through catalytic hydrogenation, that is, by hydrogenating at 20 to 80xc2x0 C. and at atmospheric pressure to 5 atm (507 KPa) in a suitable solvent, for example, ethanol, methanol, acetic acid or the like in the presence of a suitable catalyst, for example, palladium on carbon, platinum oxide, rhodium on alumina or the like.
Moreover, compounds represented by the general formula (19) can be synthesized by reducing compounds represented by a general formula (31) 
(wherein A, Y, V, T, R1 and R2 are as described above), through catalytic hydrogenation, that is, by hydrogenating at 20 to 80xc2x0 C. and at ambient pressure to 5 atm (507 KPa) in a suitable solvent, for example, ethanol, methanol, acetic acid or the like in the presence of a suitable catalyst, for example, palladium on carbon, platinum oxide, rhodium on alumina or the like.
Moreover, compounds, A being single bond among compounds represented by the general formula (31), can be synthesized by reacting compounds represented by a general formula (32) 
(wherein R1 and R2 are as described above), with compounds represented by the general formula (21) 
(wherein Y, V and T are as described above), for 2 to 10 hours at 25 to 150xc2x0 C. in a suitable solvent, for example, N,N-dimethylformamide, acetonitrile or the like, in the presence of organic base, for example, triethylamine or the like.
Here, the general formula (23) or general formula (32) can be synthesized by reacting a general formula (33) or general formula (34) 
(wherein Q and R1 are as described above), with alkyl halide, for example, methyl iodide or the like, or aralkyl halide, for example, 4-methoxybenzyl chloride or the like for 2 to 10 hours at 20 to 120xc2x0 C. in a suitable solvent, for example, benzene, toluene, chloroform, methylene chloride, tetrahydrofuran or the like, using a suitable silver catalyst, for example, silver oxide, silver carbonate or the like.
Moreover, they can also be synthesized by reacting compounds represented by the general formula (33) or general formula (34) for 2 to 6 hours at 0 to 120xc2x0 C. in a suitable solvent, for example, benzene, toluene, chloroform, methylene chloride, tetrahydrofuran or the like, using borate, for example, tetramethyloxonium borate or the like.
Moreover, the general formula (34) can be synthesized through synthetic processes shown by following scheme. 
(R denotes a lower alkyl group)
Moreover, compounds, A being single bond among compounds represented by the general formula (26), can be synthesized through processes shown by following scheme. 
(wherein Q, P1 and P2 are as described above, A1 denotes single bond, and Xc denotes a halogen atom)
Namely, a general formula (39) synthesizable through already known process are reacted with compounds represented by the general formula (21) 
(wherein Y, T and V are as described above), for 2 to 10 hours at 25 to 150xc2x0 C. in a suitable solvent, for example, N,N-dimethylformamide, acetonitrile or the like in the presence of organic base, for example, triethylamine or the like to convert to general formula (40). This general formula (40) is reduced, for example, through catalytic hydrogenation, that is, by hydrogenating at 20 to 80xc2x0 C. and at atmospheric pressure to 5 atm (507 KPa) in a suitable solvent, for example, ethanol, methanol, acetic acid or the like in the presence of a suitable catalyst, for example, palladium on carbon, platinum oxide, rhodium on alumina or the like to convert to general formula (41) (if need be, amino group is protected according to usual process), and this is reacted for 0.5 to 2 hours at xe2x88x9210 to 80xc2x0 C. without solvent or in a suitable solvent, for example, concentrated sulfuric acid, carbon disulfide, acetic acid or the like, using a suitable nitrating agent, for example, concentrated nitric acid, fuming nitric acid, potassium nitrate or the like, thus making it possible to synthesize.